Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1^G93A mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1^G93A ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1^G93A mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1^G93A ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research.

肌萎缩侧索硬化 (ALS) 是最常见的运动神经元疾病，目前仍缺乏有效的治疗选择。ALS 以散发性和家族性形式出现，临床上无法区分；大约 20% 的家族性 ALS 病例与超氧化物歧化酶 1 (SOD1) 基因的突变有关。Fenretinide (FEN) 是目前用于多项临床试验的癌症化学预防和抗增殖剂，是一种多靶点药物，也具有氧化还原调节活性。我们分析了 FEN 对运动神经元 (NSC34) 和肌肉 (C2C12) 细胞系中突变 SOD1 (mSOD1) 毒性的影响，并评估了长期施用新型纳米胶束芬维A胺制剂 (NanoMFen) 对 SOD1 ^{G93A 中}ALS 疾病进展的影响老鼠模型。结果表明，FEN显着阻止了NSC34运动神经元中mSOD1表达的毒性；此外，FEN 能够部分克服 mSOD1 对 C2C12 肌肉细胞的生肌程序的毒性作用。NanoMFen 的给药改善了疾病进展并增加了 mSOD1 ^G93A ALS 小鼠的中位存活率，即使在疾病发作后给药也是如此；然而，对 ALS 小鼠的有益影响仅限于女性。我们的数据支持 FEN 对 ALS 相关 SOD1 ^G93A突变蛋白毒性的治疗潜力，并促进进一步研究以阐明该药物在 ALS 中的特定细胞靶点。此外，NanoMFen 在 mSOD1 ^{G93A 中}的性别相关功效 从精准医学方法的角度来看，ALS 小鼠加强了性别药理学在 ALS 研究中的重要性。